Pain usually falls into one of two categories:
Nociceptive pain is caused by damage to body tissue and usually described as a sharp, aching, or throbbing pain. This kind of pain can be due to benign pathology; or by tumors or cancer cells that are growing larger and crowding other body parts near the cancer site. Nociceptive pain may also be caused by cancer spreading to the bones, muscles, or joints, or that causes the blockage of an organ or blood vessels.
Neuropathic pain occurs when there is actual nerve damage. Nerves connect the spinal cord to the rest of the body and allow the brain to communicate with the skin, muscles and internal organs. Nutritional imbalance, alcoholism, toxins, infections or auto-immunity can all damage this pathway and cause pain. Neuropathic pain can also be caused by a cancer tumor pressing on a nerve or a group of nerves. People often describe this pain as a burning or heavy sensation, or numbness along the path of the affected nerve. The two types of pain are not necessarily mutually exclusive. Cancer pain for example can be nociceptive or neuropathic, or both.
The capacity to experience pain has a protective role: it warns us of imminent or actual tissue damage and elicits coordinated reflex and behavioural responses to keep such damage to a minimum. If tissue damage is unavoidable, a set of excitability changes in the peripheral and central nervous system establish a profound but reversible pain hypersensitivity in the inflamed and surrounding tissue. This process assists wound repair because any contact with the damaged part is avoided until healing has occurred. By contrast, persistent pain syndromes offer no biological advantage and cause suffering and distress. Such maladaptive pain typically results from damage to the nervous system—the peripheral nerve, the dorsal root ganglion or dorsal root, or the central nervous system—and is known as neuropathic pain. Such syndromes comprise a complex combination of negative symptoms or sensory deficits, such as partial or complete loss of sensation, and positive symptoms that include dysaethesia, paraesthesia, and pain.
Apart from trigeminal neuralgia, which responds well to carbamazepine, pharmacotherapy for neuropathic pain has been disappointing. Patients with neuropathic pain for example do not respond to non-steroidal anti-inflammatory drugs and resistance or insensitivity to opiates is common. Patients are usually treated empirically with tricyclic or serotonin and norepinephrine uptake inhibitors, antidepressants, and anticonvulsants that all have limited efficacy and undesirable side-effects. Neurosurgical lesions have a negligible role and functional neurosurgery, including dorsal column or brain stimulation, is controversial, although transcutaneous nerve stimulation may provide some relief. Local anaesthetic blocks targeted at trigger points, peripheral nerves, plexi, dorsal roots, and the sympathetic nervous system have useful but short-lived effects; longer lasting blocks by phenol injection or cryotherapy risk irreversible functional impairment and have not been tested in placebo-controlled trials. Chronic epidural administration of drugs such as clonidine, steroids, opioids, or midazolam is invasive, has side-effects, and the efficacy of these drugs has not been adequately assessed.
Pathological pain is characterized by extensive modification of the systems involved in pain signal transmission and modulation at the spinal level (primary sensory neurons and the spinal cord) and probably in the brain. Chronic pain, particularly of neuropathic origin, may also lead to tissue remodeling (plasticity). This may include, for instance, loss of spinal interneurons, abnormal rearrangement of central afferents of primary sensory neurons and glial cell activation and proliferation. These long-lasting modifications are mediated by, or associated with, changes in the production of key molecules involved in nociceptive processing. Gene-based techniques allow local or even cell-type-specific interventions to be used to correct the abnormal production of some of these proteins, modulate the activity of signal transduction pathways or overproduce various therapeutic secreted proteins. In fact, with these approaches, it may be possible to not ‘only’ relieve established ongoing pain but to reverse the pathological situation underlying chronic pain (Meunier and Pohl; Gene Therapy (2009) 16, 476-482).
There is no treatment to prevent the development of neuropathic or nociceptive pain, nor to adequately, predictably, and specifically control established neuropathic or nociceptive pain. The aim of existing treatment, therefore, is often just to help the patient cope by means of psychological or occupational therapy, rather than to eliminate the pain. Thus, there is an unmet clinical need and a challenge to develop more effective therapy. This invention is directed to an RNA interference (RNAi) agent and the use of that RNAi agent to prevent, manage or treat pain in individuals.
The RNAi pathway is initiated by the enzyme Dicer, which cleaves double-stranded RNA (dsRNA) molecules into short fragments (commonly referred to as siRNAs) of ˜20-25 nucleotides. One of the two strands of each fragment, known as the guide strand or active strand, is then incorporated into the RNA-induced silencing complex (RISC) through binding to a member of the argonaute protein family. After integration into the RISC, the guide strand base-pairs with its target mRNA and is thought to either inhibit a target by inhibiting translation (by stalling the translational machinery) and/or inducing cleavage of the mRNA, thereby preventing it from being used as a translation template.
While the fragments produced by Dicer are double-stranded, only the guide strand, directs gene silencing. The other anti-guide strand referred to commonly as a passenger strand, carrier strand or * strand is frequently degraded during RISC activation (Gregory R et al., 2005). RISC assembly is thought to be governed by an enzyme that selects which strand of a dsRNA Dicer product is loaded into RISC. This strand is usually the one whose 5′ end is less tightly paired to its complement. There also appears to be a clear bias for A, and to a lesser extent U, at the 5′ position to facilitate binding to some argonaute proteins (Schwarz D S et al., 2003; Frank F et al., 2010).
Reference to any prior art in the specification is not, and should not be taken as, an acknowledgment or any form of suggestion that this prior art forms part of the common general knowledge in Australia or any other jurisdiction or that this prior art could reasonably be expected to be ascertained, understood and regarded as relevant by a person skilled in the art.